The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep ), mouse cripto (Cr-1) and cryptic and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the embryonic anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right asymmetry. In the mouse cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1 transduced mammary epithelial cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in b-catenin adherens function and an increase in vimentin expression. Expression of CR-1 is increased several-fold in human colon, gastric, pancreatic, cervical, ovarian and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase in cripto-1 expression can first be detected in premalignant lesions in some of these tissues such as in the breast ( hyperplasias and DCIS ), colon ( adenomas ) and stomach ( intestinal metaplasias ). Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAPK signaling pathway in mammary epithelial cells. Activation of PI-3 kinase, GSK-3b and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of b-casein and whey acidic protein. In mammary epithelial cells part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or FGFR-1 through a src-like tyrosine kinase.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009003-18
Application #
6433130
Study Section
(LTIB)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Normanno, Nicola; De Luca, Antonella; Bianco, Caterina et al. (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2-16
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Strizzi, Luigi; Bianco, Caterina; Normanno, Nicola et al. (2005) Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis. Oncogene 24:5731-41
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Bianco, Caterina; Strizzi, Luigi; Normanno, Nicola et al. (2005) Cripto-1: an oncofetal gene with many faces. Curr Top Dev Biol 67:85-133
Sun, Youping; Strizzi, Luigi; Raafat, Ahmed et al. (2005) Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis. Am J Pathol 167:585-97
Bianco, Caterina; Strizzi, Luigi; Ebert, Andreas et al. (2005) Role of human cripto-1 in tumor angiogenesis. J Natl Cancer Inst 97:132-41

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